Process for making silicone intraocular lens with blue light absorption properties

ABSTRACT

A process for producing silicone intraocular lenses (IOLs) capable of absorbing blue light. Intraocular lenses so produced block blue light from reaching the retina of an eye implanted with the IOL. By blocking blue light from reaching the retina, the IOL thereby prevents potential damage to the retina.

FIELD OF THE INVENTION

The present invention relates to a process for making siliconeintraocular lenses with blue light absorption properties. Moreparticularly, the present invention relates to a process for reacting asilicone intraocular lens with an ethyleneically unsaturated yellow dyeto produce an intraocular lens capable of blocking blue light.

BACKGROUND OF THE INVENTION

Since the 1940's optical devices in the form of intraocular lens (IOL)implants have been utilized as replacements for diseased or damagednatural ocular lenses. In most cases, an intraocular lens is implantedwithin an eye at the time of surgically removing the diseased or damagednatural lens, such as for example, in the case of cataracts. Fordecades, the preferred material for fabricating such intraocular lensimplants was poly(methyl methacrylate), which is a rigid, glassypolymer.

Softer, more flexible IOL implants have gained in popularity in morerecent years due to their ability to be compressed, folded, rolled orotherwise deformed. Such softer IOL implants may be deformed prior toinsertion thereof through an incision in the cornea of an eye. Followinginsertion of the IOL in an eye, the IOL returns to its originalpre-deformed shape due to the memory characteristics of the softmaterial. Softer, more flexible IOL implants as just described may beimplanted into an eye through an incision that is much smaller, i.e.,less than 4.0 mm, than that necessary for more rigid IOLs, i.e., 5.5 to7.0 mm. A larger incision is necessary for more rigid IOL implantsbecause the lens must be inserted through an incision in the corneaslightly larger than the diameter of the inflexible IOL optic portion.Accordingly, more rigid IOL implants have become less popular in themarket since larger incisions have been found to be associated with anincreased incidence of postoperative complications, such as inducedastigmatism.

With recent advances in small-incision cataract surgery, increasedemphasis has been placed on developing soft, foldable materials suitablefor use in artificial IOL implants. Mazzocco, U.S. Pat. No. 4,573,998,discloses a deformable intraocular lens that can be rolled, folded orstretched to fit through a relatively small incision. The deformablelens is inserted while it is held in its distorted configuration, thenreleased inside the chamber of the eye, whereupon the elastic propertyof the lens causes it to resume its molded shape. As suitable materialsfor the deformable lens, Mazzocco discloses polyurethane elastomers,silicone elastomers, hydrogel polymer compounds, organic or syntheticgel compounds and combinations thereof.

In recent years, blue light (400-500 nm) has been recognized as beingpotentially hazardous to the retina. Accordingly, yellow dyes to blockblue light have been used in foldable intraocular lenses, in conjunctionwith ultraviolet light absorbers, to avoid potential damaging effects.Freeman et al., U.S. Pat. No. 6,353,069, disclose high refractive indexcopolymers comprising two or more acrylate and/or methacrylate monomerswith aromatic groups. Ophthalmic devices made of the copolymers may alsoinclude colored dyes, such as the yellow dyes disclosed in U.S. Pat. No.5,470,932. Such materials exhibit sufficient strength to allow devicesmade of them, such as intraocular lenses, to be folded or manipulatedwithout fracturing.

Because of shortcomings in the properties of many soft, flexiblematerials used in the manufacture of ophthalmic devices, such as theformation of water vacuoles or “glistenings”, and low refractive index,which requires a lens to be relatively thick in order to provide a lensof proper refractive power, new materials and methods of manufacturingof ophthalmic devices are needed.

SUMMARY OF THE INVENTION

Soft, foldable, high refractive index, silicone intraocular lenses(IOLs) capable of absorbing blue light are prepared in accordance withthe present invention through a coating process using a reactive yellowdye solution having blue light blocking properties. The blue lightabsorbing IOLs produced in accordance with the present invention protectan eye's retina from potentially damaging blue light and therebypossibly providing protection from macular degeneration.

Blue light blocking silicone IOLs of the present invention are producedby exposing a semi-finished silicone IOL to an ethyleneicallyunsaturated yellow dye-containing solution and allowing the same toundergo a hydrosilation reaction. Such production process yieldssilicone IOLs with blue light absorbing properties. By absorbing bluelight, the IOL serves to block blue light from reaching and potentiallydamaging the retina of an eye implanted with the IOL. Silicone IOLs soproduced are transparent, relatively high in elongation and relativelyhigh in refractive index.

Accordingly, it is an object of the present invention to provide aprocess for the production of silicone IOLs capable of absorbing bluelight.

Another object of the present invention is to provide a process for theproduction of silicone IOLs having relatively high refractive indicesand good clarity.

Another object of the present invention is to provide a process for theproduction of silicone IOLs that are flexible.

Still another object of the present invention is to providebiocompatible silicone IOLs capable of absorbing blue light.

These and other objectives and advantages of the present invention, someof which are specifically described and others that are not, will becomeapparent from the detailed description and claims that follow.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the production ofhigh refractive index silicone IOLs capable of absorbing blue light andthereby blocking blue light from reaching the retina of an eye implantedwith the IOL. Silicone IOLs of the present invention are produced byallowing a semi-finished silicone IOL to react with an ethyleneicallyunsaturated dye through a hydrosilation reaction. The subject processfor treating silicone IOLs is relatively simple and producesbiocompatible silicone IOLs capable of absorbing blue light.

A “semi-finished” silicone IOL for purposes of the present invention, isa silicone IOL having free hydrosilyl groups. By dipping a semi-finishedsilicone IOL in a weak solvent, such as for example but not limited tomethylene chloride, containing a one or more reactive dyes, such as areactive yellow dye, and one or more platinum catalysts, followed bythermal treatment of the IOL in an oven at a low temperature, preferablyless than approximately 100° C. for a relatively short period of time,preferably less than several hours and more preferably less thanapproximately 30 minutes, a quantitative amount of dye can beincorporated into or coat the IOL. There are several platinum catalystsor catalyst systems suitable for the hydrosilation reaction of thepresent invention, depending on the reaction temperature and kineticsdesired. For example, platinum (3 to 3.5%)-divinyltetramethyldisiloxanecomplex is suitable for use in a room temperature reaction. Platinum (3to 3.5%)-cyclovinylmethylsiloxane complex is suitable for use in areaction at a moderate temperature of 50 to 100° C. The reactionkinetics can be regulated through the concentration of the catalyst andthrough the addition of various amounts of one or more inhibitors.Suitable inhibitors include for example but are not limited to1,3-divinyltetramethyldisiloxane and1,3,5,7-tetramethyl-1,3,5,7-tetravinyl cyclosiloxane. Such inhibitorsmay be present in the catalyst complex. The chemical reaction that takesplace as a result of this process is illustrated below in ReactionScheme 1.

As depicted above in Reaction Scheme 1, Si —H represents the freehydrosilyl groups of a “semi-finished” silicone IOL, and H₂C═CR₁R₂represents a reactive yellow dye. Here, R₁ can be H or CH₃ and R₂ is agroup containing other functional groups as well as functional groupsresponsible for yellow color. The reactive yellow dye can have forexample, but is not limited to the following ethylenically unsaturatedgroups: vinyl, allyl, acrylate, methacrylate, acrylamide,methacrylamide, fumarate, maleate, itaconate, styrene, nitrile and thelike. Depending on the particular solvent and the concentration ofreactive yellow dyes in the solvent, the reactive yellow dye canpenetrate into the polymer matrix of the lens body, as well as,partially or completely coat the lens surface.

Reactive dyes useful in the manufacture of flexible, high refractiveindex silicone IOLs capable of absorbing blue light, may be preparedthrough a process of multiple chemical reaction steps. This processincludes a step for forming a blue light absorbing functional group,i.e., a dye, such as for example but not limited to a diazo coupling forazo dye formation. The process also includes a step to incorporate thecompound with a dye functional group and a reagent that is ethylenicallyunsaturated. For example, a reactive azo yellow dye having twoethylenically unsaturated groups can be prepared by reacting a yellowdye having two alcohol groups with an acid chloride or an isocyanatehaving an ethylenically unsaturated group. Such is depicted in ReactionSchemes 2 through 3 wherein a yellow dye,N,N-bis-(2-hydroxyethyl)-(4-phenylazo) aniline (Solvent Yellow 58),synthesized in accordance with the procedure of Example 1 below, is usedas an example not intended to be limiting.

Here, “Ph” represents either C₆H₅ or C₆H₄, as appropriate.

Alternatively, a reactive yellow dye with one ethylenically unsaturatedgroup useful in accordance with the present invention, such as forexample but not limited toN-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide,represented below in Formula 1,

can be prepared by first reacting vinylacetyl chloride with4-aminoethylphenol to give 4-vinylacetamidoethyl phenol, which is thencoupled with the diazonium salt of toluidine as described in more detailbelow in Example 4.

The process of the present invention for preparing flexible, highrefractive index silicone IOLs with blue light absorption properties isdescribed in still greater detail in the Examples provided below.

EXAMPLE 1 Synthesis of N,N-Bis-(2-Hydroxyethyl)-(4-Phenylazo)Aniline(Solvent Yellow 58)

The synthesis of N,N-bis-(2-hydroxyethyl)-(4-phenylazo) aniline isaccomplished by coupling the diazonium salt of aniline with N-phenyldiethanolamine. A detailed procedure is also described in D. L.Jinkerson, U.S. Pat. No. 5,470,932, incorporated herein in its entiretyby reference.

EXAMPLE 2 Synthesis ofN,N-Bis-(2-Allylcarbamatoethyl)-(4′-Phenylazo)Aniline

A 1000-mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.7grams (0.02 mole) of N,N-bis-(2-hydroxyethyl)-(4-phenylazo)aniline, 3.28g of allyl isocyanate (0.04 mole) (Aldrich Chemical, Inc., Milwaukee,Wis.) and 0.014 g of dibutyltin dilaurate (Aldrich Chemical). Themixture is heated and refluxed overnight under vigorous stirring. Themixture is then checked with infrared spectroscopy and no residualisocyanate peak is found indicating the reaction is complete. Themixture is concentrated using a rotavapor. High performance liquidchromatography (HPLC) analysis indicates only one major product. Theproduct is then passed through silica gel chromatography to give finalpurified product with a yield of at least 80 percent. The product isidentified by nuclear magnetic resonance (NMR) and Mass Spectroscopy.

EXAMPLE 3 Synthesis ofN,N-Bis-(2-Vinylacetoxyethyl)-(4′-Phenylazo)Aniline

A 1000-mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.7grams (0.02 mole) of N,N-bis-(2-hydroxyethyl)-(4-phenylazo) aniline and4.04 grams of triethylamine (0.04 mole). The contents are chilled withan ice bath. Through a dropping funnel, 4.18 g (0.04 mole) ofvinylacetyl chloride is added into the flask over a period of 30minutes. The ice bath is then removed and the contents are continuouslystirred overnight. The mixture is then filtered and then condensed usinga rotavapor. HPLC analysis indicates only one major product. The productis then passed through silica gel chromatography to give a finalpurified product with a yield of at least 80 percent. The product isidentified by NMR and Mass Spectroscopy.

EXAMPLE 4 Synthesis ofN-2-[3′-2″-Methylphenylazo)-4′-Hydroxyphenyl]Ethyl Vinylacetamide

N-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide canbe made in two steps. The first step is the formation of4-vinylacetamidoethyl phenol. The second step is the coupling of azoniumsalt of toluidine with the phenol to give the product.

Step 1. Synthesis of 4-vinylacetamidoethyl phenol.

A 1000-mL 3-neck, round bottom flask connected with a reflux condenserand a drying tube, is charged with 250 mL of methylene chloride, 5.48grams (0.04 mole) 4-aminoethylphenol and 4.04 grams (0.04 mole)triethylamine. The contents are chilled with an ice bath. Through adropping funnel, 4.18 g (0.04 mole) of vinylacetyl chloride is addedinto the flask over a period of 30 minutes. The ice bath is then removedand the contents are continuously stirred overnight. The mixture is thenfiltered and then condensed using a rotavapor. High performance liquidchromatography (HPLC) analysis indicates only one major product. Theproduct is then passed through silica gel chromatography to give a finalpurified product with a yield of at least 80 percent. The product isidentified by NMR and Mass Spectroscopy.

Step 2. Coupling of product from Step 1 with toluidine diazonium salt.

The procedure is about the same as that described in D. L. Jinkerson,U.S. Pat. No. 5,470,932, Example 1, second half. The difference is that4-Vinylacetamidoethyl phenol is used to replace the acrylamidoethylphenol. The product is identified by NMR and Mass Spectroscopy.

EXAMPLE 5 Preparation of Yellow Dye Solution for Coating of an IOL

Solutions containing 0.1, 0.5, 1, 2 and 5 weight percent of the yellowdye of Example 4 in methylene chloride are prepared. To these solutions,platinum-cyclovinylmethylsiloxane complex (Gelest, Inc., Tullytown, Pa.)at 1% of the weight of the yellow dye is also added.

EXAMPLE 6 Coating of Silicone Intraocular Lenses

Ten (10) freshly thermally cured SoFleX™ Model LI61 U (Bausch & Lomb,Incorporated, Rochester, N.Y.) lenses are submerged into each coatingsolution as described in Example 3 for 30, 60 and 120 minutes. Thelenses are then removed from the coating solutions and air dried. Thelenses are then placed in an oven at 80 to 90° C. for an hour. Theselenses are then subjected to standard processing to get the finalfinished product.

Model LI61 U lenses are silicone IOLs derived from components consistingof a vinyl terminated polydimethyl-co-diphenyl siloxane, silicon-basedreinforcing resins with vinyl groups, and an oligomer with multihydrosilane units. Model LI61 U silicone lenses have excess freehydrosilane groups after curing.

EXAMPLE 7 Selection of Yellow Dye Concentration and Coating Conditions

Run ultraviolet (UV) and visible absorption spectroscopy of coatedlenses before and after processing. Select the yellow dye concentrationand residence time of lens in dye solution based on the visible lightabsorption of the process lenses between 400-500 nm. Conditions, whichgive about or less than 50% transmittance and maintenance of lenspower/cosmetics are chosen for further coating studies, followed byoptimization of conditions.

Soft, foldable, relatively high refractive index of approximately 1.42or greater, relatively high elongation of approximately 100 percent orgreater, silicone IOLs with blue light absorption properties aresynthesized through the process of the present invention. Suitablecatalysts for use in the process of the present invention include butare not limited to platinum (3-3.5%)-divinyltetramethyldisiloxanecomplex and platinum (3-3.5%)-cyclovinylmethylsiloxane complex.

The silicone IOLs produced as described herein have the flexibilityrequired to allow the same to be folded or deformed for insertion intoan eye through the smallest possible surgical incision, i.e., 3.5 mm orsmaller. It is unexpected that the subject silicone IOLs describedherein could possess the ideal physical properties disclosed herein. Theideal physical properties of the subject silicone IOLs are unexpectedbecause changes in mechanical properties such as modulus, percentelongation and tear strength can occur upon addition of the reactive dyefunctional groups.

Silicone IOLs treated using the process of the present invention can beof any design capable of being rolled or folded for implantation througha relatively small surgical incision, i.e., 3.5 mm or less. Such IOLsmay be manufactured to have an optic portion and haptic portions made ofthe same or differing materials. Once the material(s) are selected, thesame may be cast in molds of the desired shape, cured and removed fromthe molds. After such molding, the IOLs are treated in accordance withthe process of the present invention and then cleaned, polished,packaged and sterilized by customary methods known to those skilled inthe art.

In addition to IOLs, the process of the present invention is alsosuitable for use in the production of other medical or ophthalmicdevices such as contact lenses, keratoprostheses, capsular bag extensionrings, corneal inlays, corneal rings and like devices.

Silicone IOLs manufactured using the process of the present inventionare used as customary in the field of ophthalmology. For example, in asurgical cataract procedure, an incision is placed in the cornea of aneye. Through the corneal incision the cataractous natural lens of theeye is removed (aphakic application) and an IOL is inserted into theanterior chamber, posterior chamber or lens capsule of the eye prior toclosing the incision. However, the subject ophthalmic devices maylikewise be used in accordance with other surgical procedures known tothose skilled in the field of ophthalmology.

While there is shown and described herein a process for producingsilicone IOLs with blue light absorption properties, it will be manifestto those skilled in the art that various modifications may be madewithout departing from the spirit and scope of the underlying inventiveconcept and that the same is not limited to particular processes andstructures herein shown and described except insofar as indicated by thescope of the appended claims.

1. A method for treating medical devices comprising: exposing asemi-finished silicone medical device to a solution containing one ormore reactive dyes and one or more catalysts.
 2. A method for treatingmedical devices to render said devices capable of absorbing blue lightcomprising: exposing a semi-finished silicone medical device to asolution containing one or more reactive dyes and one or more catalysts.3. The method of claim 1 or 2 wherein said medical device is selectedfrom the group consisting of contact lenses, keratoprostheses, capsularbag extension rings, corneal inlays and corneal rings.
 4. The method ofclaim 1 or 2 wherein said medical device is an intraocular lens.
 5. Themethod of claim 1 or 2 wherein said reactive dyes having ethylenicallyunsaturated groups are selected from the group consisting of vinyl,allyl, acrylate, methacrylate, acrylamide, methacrylamide, fumarate,maleate, itaconate, styrene and nitrile.
 6. The method of claim 1 or 2wherein said catalysts are selected from the group consisting ofplatinum (3-3.5%)-divinyltetramethyldisiloxane complex and platinum(3-3.5%)-cyclovinylmethylsiloxane complex.
 7. The method of claim 1 or 2wherein said catalysts is a platinum catalyst.
 8. The method of claim 1or 2 wherein said medical device is thermally treated at a temperatureless than about 100° C.
 9. The method of claim 1 or 2 wherein saidmedical device is thermally treated at a temperature of about 80 to 90°C.
 10. The method of claim 1 or 2 wherein said medical device isthermally treated for about 30 minutes.
 11. The method of claim 1 or 2wherein said medical device is thermally treated for a period of timeless than several hours.
 12. The method of claim 1 or 2 wherein saidmedical device is thermally treated for about 120 minutes or less.
 13. Aprocess for producing a medical device capable of absorbing blue lightcomprising: exposing a medical device with free reactive groups to asolution containing one or more reactive dyes and one or more catalysts.14. The process of claim 13 wherein said free reactive groups are freehydrosilyl groups.
 15. The process of claim 13 wherein said medicaldevice is selected from the group consisting of contact lenses,keratoprostheses, capsular bag extension rings, corneal inlays andcorneal rings.
 16. The process of claim 13 wherein said medical deviceis an intraocular lens.
 17. The process of claim 13 wherein saidreactive dyes having ethylenically unsaturated groups are selected fromthe group consisting of vinyl, allyl, acrylate, methacrylate,acrylamide, methacrylamide, fumarate, maleate, itaconate, styrene andnitrile.
 18. The process of claim 13 wherein said catalysts are selectedfrom the group consisting of platinum(3-3.5%)-divinyltetramethyldisiloxane complex and platinum(3-3.5%)-cyclovinylmethylsiloxane complex.
 19. The process of claim 13wherein said catalysts is a platinum catalyst.
 20. The process of claim13 wherein said medical device is thermally treated at a temperatureless than about 100° C.
 21. The process of claim 13 wherein said medicaldevice is thermally treated at a temperature of about 80 to 90° C. 22.The process of claim 13 wherein said medical device is thermally treatedfor about 30 minutes.
 23. The process of claim 13 wherein said medicaldevice is thermally treated for a period of time less than severalhours.
 24. The process of claim 13 wherein said medical device isthermally treated for about 120 minutes or less.
 25. A method of usingthe medical device produced through the method of claim 1 or 2comprising: implanting said medical device surgically within an eye. 26.A method of using the medical device produced through the process ofclaim 13 comprising: implanting said medical device surgically within aneye.
 27. The method of claim 1 or 2 wherein said catalyst includes oneor more inhibitors.
 28. The method of claim 1 or 2 wherein said catalystincludes one or more inhibitors selected from the group consisting of1,3-divinyltetramethyldisiloxane and1,3,5,7-tetramethyl-1,3,5,7-tetravinyl cyclosiloxane.
 29. The process ofclaim 13 wherein said catalysts include one or more inhibitors.
 30. Theprocess of claim 13 wherein said catalysts include one or moreinhibitors selected from the group consisting of1,3-divinyltetramethyldisiloxane and1,3,5,7-tetramethyl-1,3,5,7-tetravinyl cyclosiloxane.
 31. A medicaldevice comprising: a medical device treated with at least one reactivedye so that said medical device has blue light absorption properties.32. The medical device of claim 31 wherein said medical device isfabricated from semi-finished silicone.
 33. The medical device of claim31 wherein said at least one reactive dye having ethylenicallyunsaturated groups is selected from the group consisting of vinyl,allyl, acrylate, methacrylate, acrylamide, methacrylamide, fumarate,maleate, itaconate, styrene and nitrile.
 34. The medical device of claim31 wherein said reactive dye is a reactive yellow dye.
 35. The medicaldevice of claim 31 wherein said reactive dye has either one or twoethylenically unsaturated groups.
 36. The medical device of claim 31wherein said reactive dye is selected from the group consisting ofN,N-bis-(2-allylcarbamatoethyl)-(4′-phenylazo)aniline andN,N-bis-(2-vinylacetoxyethyl)-(4′-phenylazo)aniline andN-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide. 37.The medical device of claim 31 wherein said reactive dye undergoes ahydrosilation reaction with said medical device.
 38. The medical deviceof claim 31 wherein said reactive dye penetrates into the polymer matrixof said medical device.
 39. The medical device of claim 31 wherein saidreactive dye partially or completely coats the surface of said medicaldevice.
 40. An intraocular lens comprising: an intraocular lens treatedwith at least one reactive dye so that said intraocular lens has bluelight absorption properties.
 41. The intraocular lens of claim 40wherein said medical device is fabricated from semi-finished silicone.42. The intraocular lens of claim 40 wherein said reactive dye havingethylenically unsaturated groups is selected from the group consistingof vinyl, allyl, acrylate, methacrylate, acrylamide, methacrylamide,fumarate, maleate, itaconate, styrene and nitrile.
 43. The intraocularlens of claim 40 wherein said reactive dye is a reactive yellow dye. 44.The intraocular lens of claim 40 wherein said reactive dye is selectedfrom the group consisting ofN,N-bis-(2-allylcarbamatoethyl)-(4′-phenylazo)aniline andN,N-bis-(2-vinylacetoxyethyl)-(4′-phenylazo)aniline andN-2-[3′-(2″-methylphenylazo)-4′-hydroxyphenyl]ethyl vinylacetamide. 45.The intraocular lens of claim 40 wherein said reactive dye undergoes ahydrosilation reaction with said medical device.
 46. The intraocularlens of claim 40 wherein said reactive dye penetrates into the polymermatrix of said medical device.
 47. The intraocular lens of claim 40wherein said reactive dye partially or completely coats the surface ofsaid medical device.